Fampridine Modulates Thalamic Resting State Functional Connectivity and Ameliorates Fatigue in Multiple Sclerosis Patients (P4.005)

OBJECTIVE: To investigate the effects of fampridine and amantadine on thalamic resting state (RS) functional connectivity (FC) in patients with multiple sclerosis (MS) and fatigue. BACKGROUND: In MS, thalamic dysfunction has been associated with fatigue. DESIGN/METHODS: Forty-five fatigued MS patients were randomly, blindly assigned to undergo treatment with fampridine (n=15), amantadine (n=15) or placebo (n=15) and underwent clinical, neuropsychological (including fatigue assessment) and 3T RS functional MRI (fMRI) at baseline (T0) and after four weeks (W4) of treatment. Fifteen matched healthy controls were also studied. RS FC analysis was done using the left thalamus as seed region. RS FC between- and within-group analyses, and correlations between changes of Modified Fatigue Impact Scale (MFIS) and RS FC changes were assessed (SPM8). RESULTS: At T0, compared with controls, MS patients showed decreased thalamic RS FC with temporal, occipital, frontal and cerebellar regions. At W4, fampridine patients showed significantly increased global, physical and cognitive MFIS (p=0.003/0.004/0.02), while no significant MFIS changes were observed in amantadine patients. Placebo patients showed improved global, physical and psycho-social MFIS (p=0.02/0.01/0.02). In fampridine patients, increased thalamic RS FC at W4 was detected with bilateral temporal, frontal and parahippocampal regions, while amantadine patients and healthy controls showed no significant RS FC modifications. In placebo patients, small clusters of increased thalamic FC with frontal and parietal regions were detected. Compared to the other groups, fampridine patients showed a significant RS FC increase over time in the left insula and fusiform gyrus, and in the right precentral and hyppocampal gyrus. Physical MFIS improvements were associated with increased thalamo-cerebellar FC, while cognitive MFIS improvements were associated with increased thalamo-frontal FC. CONCLUSIONS: Treatment with fampridine ameliorates fatigue in MS patients possibly through a modulation of thalamic functional connections. Study Supported by: Partially supported by a grant from Italian Ministry of Health (GR-2008-1138784).